During the last funding period we demonstrated that co-operation between CD4+ and CD8+ T lymphocytes is essential for control of HCV infection in chimpanzees. The collective goal of the three Projects comprising this HCCRC renewal application is to understand why innate and adaptive cellular immune responses often fail in the acute phase of infection. With regard to the adaptive response CD4+ T cell failure is a central event causing HCV persistence and we seek to define mechanisms that contribute to their loss. Consequences of CD4+ T cell silencing for the CD8+ T cell response will also be investigated, including defects in differentiation or function, narrowing of the TcR clonotypic diversity, and escape mutation in MHC class I epitopes. We will also examine whether imprinting of HCV with adaptive mutations in MHC class I and II epitopes could subvert protective immune responses when the virus is transmitted to immune hosts. Finally we w ill take advantage of the chimpanzee model to investigate mechanisms underlying the genetic association between natural killer (NK) activating and inhibitory receptors and HCV infection outcome. Particular attention will be paid to the role of NK cells and their receptors in regulating the developing T cell response during acute hepatitis C. The overall goals of this HC-CRC are to: 1. Understand why CD4+ and CD8+ T cell responses often fail during acute hepatitis C. We will focus on mutational escape in MHC class I or II restricted epitopes and defects in their function or programmed differentiation after antigen activation. 2. Define how regulatory receptors like those encoded by the KIR and NKG2 complexes found on NK and sometimes T lymphocytes influence the course of acute HCV infection. 3. Determine if HCV variants imprinted with adaptive mutations in MHC class I and II epitopes circumvent protective memory T cell responses when transmitted to an immune host.